A study to analyze the origin of tumor cells in malignant fibrous histiocytomas. A multiparametric characterization

To study the derivation of tumor cells of malignant fibrous histiocytomas (MFH), their phenotypical marker profile was investigated and compared with those of malignant histiocytosis (MH) and of different types of soft tissue tumors (STT). The presence of the following markers was investigated: on paraffin sections, alpha-1-antichymotrypsin (ACT); on frozen sections antigens associated with lymphocytes, macrophages and fibroblasts, the enzymes acid phosphatase, nonspecific esterase, and beta-glucuronidase; and, on isolated and cultured cells, the receptors for EA-gamma and complement. Furthermore, the capacity to phagocytose sensitized erythrocytes and carbon particles was studied in vitro. MFH tumor cells and a part of other types of STT shared the expression of ACT and lysosomal enzymes with MH. They differed, however, from MH by the absence of monocyte/macrophage-associated antigens and by the expression of fibroblast-associated antigens, which property they had in common with other STT. MFH tumor cells were not able to form rosettes or to phagocytose Ig-sensitized erythrocytes, but they showed phagocytosis of carbon particles. The results strongly indicate that MFH tumor cells originate from (primitive) fixed mesenchymal cells and are not related to monocyte-derived histiocytes.     

Malignant fibrous histiocytoma of maxillary sinus and nasopharyngeal region

Maxilla and nasopharynx are rare sites for malignant fibrous histiocytoma. They are derived from multipotential mesenchymal cells that have the ability to differentiate into two pathways, fibroblastic and/or histiocytic. The tumor has an aggressive behaviour and death usually occurs within 2 years. Two cases of MFH studied at this institution are reported here. In these cases lymphnode metastases occured in one case and recurrence in other case after surgical excision and chemotherapy. The survival period was 10 months in 1st case and in 2nd case it was 1 year 5 months.     

Myxoid variant of malignant fibrous histiocytoma: ultrastructural observations.

The ultrastructural findings in 4 cases of the myxoid variant of malignant fibrous histiocytoma (MFH) are described. Although this neoplasm is characterized by a high rate of local recurrence, the overall prognosis is considerably better than the usual nonmyxoid MFH. The neoplasm is composed of an admixture of round, stellate and multinucleated giant cells within a myxoid and well-vascularized stroma. Electron microscopy demonstrated four principal cell types: a primitive mesenchymal cell, spindle cells of fibroblastic and histiocytic nature, and multinucleated giant cells. These observations complement the light microscopic features but probably are insufficient to differentiate critically this entity from other myxomatous lesions of mesenchymal soft tissue such as myxoma, pseudosarcomatous fasciitis, myxoid liposarcoma. The polymorphic cellular composition lends support to the concept that the neoplasm is probably derived from a primitive multipotent mesenchymal cell capable of structural and functional modulation toward more cytodifferentiated forms.     

Adipogenic, osteogenic and myofibrogenic differentiations of a rat malignant fibrous histiocytoma (MFH)-derived cell line, and a relationship of MFH cells with embryonal mesenchymal, perivascular and bone marrow stem cells

Malignant fibrous histiocytoma (MFH) is regarded as an undifferentiated pleomorphic sarcoma with unproven histogenesis. We investigated pathobiological characteristics of a rat MFH cell line (MT-9). Immunocytochemically, MT-9 cells and MT-9-induced tumours reacted to vimentin, A3 (rat MFH cell-specific antibody), macrophage markers and α-SMA (myofibroblastic marker), indicating that MT-9 showed both histiocytic and (myo)fibroblastic features. Adipogenic supplement-added MT-9 showed increased accumulation of lipid droplets. Addition of BMP-2 or osteogenic supplement to MT-9 enhanced osteoblastic markers (ALP activity, osteocalcin mRNA expression and calcification). TGF-β1-treated MT-9 revealed increased numbers of α-SMA-immunopositive cells, and enhanced protein levels of α-SMA and fibronectin, indicating myofibrogenesis. In rat tissues, A3 labelled with immature mesenchymal and perivascular cells in foetuses and neonates, and with marrow stem cells in adults. c-kit mRNA expression was seen in bone marrows and MT-9. Collectively, progenitors of MFH should be sought in lineage of marrow stem cells capable of differentiating into mesenchymal cells.     

Malignant fibrous histiocytoma: a proposed cellular origin and identification of its characterizing gene transcripts

Although malignant fibrous histiocytoma (MFH) is one of the most diffuse and highly aggressive tumors among soft tissue sarcomas in adults, it is poorly characterized from the molecular point of view. The overt lack of expression of phenotypic markers in MFH cells and the hypothesis that MFH may originate from transformed multipotent stem/progenitor cells with mesenchymal features has led us to investigate this notion and search for 'MFH-specific' genes. To address this problem, we have undertaken a differential display-based three-pair comparative mRNA profiling of bone-marrow derived mesenchymal stem cells (MSC) and cells isolated by primary MFH, leiomyosarcoma and smooth muscle cells, fibrosarcoma and dermal fibroblasts. This approach highlighted pair-wise analogies in gene expression patterns between matched tumor and healthy cells and yielded direct access to 43 genes differentially expressed between MSC and MFH cells. Eleven of the identified genes were selected for comparative evaluation of their expression levels in other sarcoma types, as well as potential markers for the detection of circulating tumor cells. Several of these genes defined the stem/progenitor versus MFH cell and some of them have the potential to be exploited for disclosure of circulating sarcoma cells. The striking similarity in the gene expression patterns observed in the two cell types was further corroborated by a remarkable similarity in the cell phenotypic markers that these cells expressed ex vivo. The findings open now the possibility to examine, also functionally, genes not previously known to be implicated in MFH development and strengthen the hypothesis that MFH originates from a mesenchymal progenitor cell.     

Histiocytoid hemangioma of the heart with peripheral eosinophilia

A histiocytoid hemangioma of the heart is reported, which was found incidentally in a man with unusually high eosinophilia. The eosinophilia subsided dramatically following removal of the tumor. The "histiocytoid" or the "epithelioid" appearance of the tumor cells and the presence of vacuolated cells were the characteristic microscopic features. The endothelial origin of this tumor was verified by positive immunostaining for factor VIII-related antigen and ultrastructural demonstration of intracytoplasmic lumen formation, abundant cytoplasmic filaments, pinocytotic vesicles, and prominent basal lamina. The presence of mitotic activity, cellular pleomorphism, and tumor necrosis raised the possibility of its malignant potential. The occurrence of this tumor in the heart may be mistaken for a myxoma clinically and a metastatic carcinoma pathologically.     

Wild-type p53 gene transfer resulted in cell cycle arrest, but not apoptosis of newly established human malignant fibrous histiocytoma cell line.

We established a human malignant fibrous histiocytoma (MFH) cell line, MFH-ToE, from a tumor originally developed in the right thigh of a 78-year-old woman. The original tumor histologically consisted of histiocytic, fibroblastic and giant cells. The tumor cells showed immunoreactivity for vimentin and alpha-1-antichymotrypsin, and were positive for acid phosphatase and non-specific esterase, being compatible with MFH. Although the histology of the heterotransplanted tumor into nude mice was similar to that of the primary MFH, the population of giant cells gradually decreased along with the culture passages. Cytogenetic analysis revealed a highly aneuploid nature with varying numbers of chromosomes from 71 to 140. Chromosome 17 showed monosomy and exon 6 to 8 of p53 gene was not amplified by PCR, implying absence of p53 function. Adenovirus vector-mediated wild-type p53 gene was successfully transfected into the MFH-ToE, which showed up-regulation of P53 and P21, as well as gradual up-regulation of Bcl-2 protein. The transfection resulted in cell cycle arrest, but not apoptosis of the MFH-ToE cells. These results revealed unique properties of the MFH-ToE, which might be useful in further studies analyzing pathological and biological characteristics of MFH.     

Malignant fibrous histiocytoma. A tumor of facultative histiocytes showing mesenchymal differentiation in cultured cell lines.

The histogenesis of malignant fibrous histiocytoma (MFH) is controversial. To elucidate the cellular origin and characteristics of this neoplasm, the authors analyzed cell lines grown from 17 patients (15 soft tissue MFH and 2 bone MFH) by using light and electron microscopy, immunocytochemistry, enzyme cytochemistry, and functional tests for receptors for the Fc portion of immunoglobulin (Fc receptors) and immunophagocytosis. Each culture exhibited a storiform/pleomorphic pattern with mixed cellular populations consisting of spindle cells, polygonal cells, and bizarre giant cells; these morphologic features corresponded to the histologic characteristics of the primary tumors. The cells in each MFH line displayed histiocytic functional markers such as lysosomal enzymes, Fc receptors and immunophagocytosis. However, these cells differed from monocyte-derived macrophages (histiocytes) in immunoreactivity; the MFH cells expressed a mesenchymal antigen (FU3) distributed among perivascular cells and fibroblasts but demonstrated no positive reactions with Leu-M1 (CD15) and Leu-M3 (CD14), which recognize the cells of the monocyte-macrophage lineage. In conclusion, these findings suggest that MFH is not a tumor of true histiocytes but of facultative histiocytes showing mesenchymal differentiation in vitro. Chromosomal analysis performed in one MFH line demonstrated abnormal karyotypes; the modal chromosome number was 58, with 5 marker chromosomes.     

The significance of bone and cartilage formation in malignant fibrous histiocytoma of soft tissue

Malignant fibrous histiocytoma of soft tissues (MFH), a mesenchymal tumor of varied morphologic patterns and cell types, sometimes contains bone and cartilage. Such bony and cartilaginous elements in a pleomorphic MFH may pose a difficult diagnostic challenge. An MFH with bone and cartilage can be distinguished from extraosseous osteogenic sarcoma and chondrosarcoma on the basis of qualitative and quantitative features of the osseous and chondroid elements. Five cases of soft tissue MFH containing bone and cartilage reported here showed: 1) that the bony and cartilaginous elements are mostly metaplastic and tend to be in the pseudo-capsule or fibrous septa of the tumor; and 2) that the bony elements may show a zoning pattern with peripheral maturation similar to myositis ossificans. In a single case, there was a small amount of "tumor osteoid." However, this was focal and lacked the diffuse and finely divided or ribbon-like pattern generally associated with osteogenic sarcoma. The probability that MFH with bone and cartilage is less aggressive than soft tissue osteogenic sarcoma or chondrosarcoma underscores the importance of accurate histologic diagnosis of these tumors.     

Malignant fibrosarcomatous mesothelioma and benign pleural fibroma (localized fibrous mesothelioma) in tissue culture: a comparison of the in vitro pattern of growth in relation to the cell of origin.

Two cases of fibrous mesothelioma are presented. The first is a malignant tumor containing bundles of spindle-shaped cells with a dense reticulin network and nests of epithelial-like cells. The second is a benign tumor made up of spindle-shaped cells arranged in bundles with abundant reticulin and collagen fibers. Tissue culture in the first case revealed plagues similar to those formed by epithelial tumors. The second case had a fibroblastic pattern with single isolated spindle-shaped cells. These findings confirmed the mesothelial nature of fibrosarcomatous mesothelioma and supported the view that the so-called localized fibrous mesotheliomas could be fibroblastic neoplasms derived from the submesothelial connective tissue.     

Histiocytoid breast carcinoma: a case report with immunohistochemical and ultrastructural studies

This is the first documented report of a case of histiocytoid breast carcinoma in Japan. The patient was a 55-year-old woman with a right breast lump. An excisional biopsy revealed proliferation of histiocyte-like cells with slightly atypical nuclei within fibrous stroma. In places, tumor cells showed an invasive pattern similar to that in invasive lobular carcinoma including a targetoid pattern, as well as a focus of in situ lobular carcinoma with transition to the histiocytoid cells. Immunohistochemical stainings of the tumor cells demonstrated positive reactions for cytokeratins and epithelial membrane antigen. Gross cystic disease fluid protein 15, an apocrine marker, was almost uniformly positive in their cytoplasm. From these results, we supposed that histiocytoid breast carcinoma is a variant of invasive lobular carcinoma. Histiocytoid breast carcinoma is easily misdiagnosed as a benign lesion such as granular cell tumor or xanthoma. Points of differential diagnosis were described and we stressed that it is most important for pathologists to keep this variant in mind in order to avoid misdiagnosis.     

Malignant fibrous histiocytoma following radiation therapy and chemotherapy for Hodgkin's lymphoma

Malignant fibrous histiocytoma (MFH) originates from primitive mesenchymal cells and has the capacity for dual differentiation into histiocytes and fibroblasts. MFH occurring as a secondary malignancy following radio-chemotherapy is rare and its exact incidence is not yet known. Here we report a case of a 42-year-old man who developed MFH in his right knee over a period of more than 10 years after radio (44 Gy)-chemotherapy to treat Hodgkin's lymphoma. After the diagnosis the patient did not return and was lost to follow-up. This is a rare case with unusual presentation, and it highlights the importance of the awareness and prevention of such secondary tumors.     

Multiple marker studies on a malignant fibrous histiocytoma with primary cutaneous localization

Continuing controversy exists concerning a possible relation between neoplastic cells of malignant fibrous histiocytoma (MFH) and the mononuclear phagocyte system. The aim of this study was to investigate the membrane and cytoenzymatic phenotype of a primary cutaneous MFH, storiform pleomorphic type, and to compare these data with ultrastructural observations. Cytoplasmic proteins (acid phosphatase, non specific esterase, alpha-1 antitrypsin, and lysozyme) suggestive of a mononuclear phagocyte origin were demonstrated in varying amounts in neoplastic cells infiltrating the dermis. Consistent with these data, two (LeuM3 and OKM5) out of four (OKM1 and LeuM1) monoclonal antibodies directed against mononuclear phagocyte antigens stained most of the neoplastic cells. Class II MCH antigens (DR and DQ) were variably expressed on distinct groups of neoplastic cells, suggesting different activation/differentiation states. The results favor the view that the present case of primary cutaneous MFH was of mononuclear phagocyte origin. However, the observed phenotypic profile was expressed on neoplastic cells irrespective of their ultrastructural morphology (histiocytic or fibroblastic). Together with previous data in the literature, the latter finding corroborates the view that distinction between these two cell types in MFH is likely to reflect divergent growth and differentiation patterns rather than histogenesis.     

乳腺恶性纤维组织细胞瘤免疫组化研究（附8例报告）

应用ＡＢＣ法，对８例乳腺恶性纤维组织细胞瘤进行ＡＡＴ、ＡＡＣＴ、Ｖｉｍ、Ｄｅｓ、Ｋｅｒ、ＣＥＡ和ＥＭＡ免疫组化染色。结果ＡＡＴ、ＡＡＣＴ和Ｖｉｍ阳性率１００％，２例Ｄｅｓ阳性。作者同意恶纤组来源于原始间叶细胞，在不同情况下可向组织细胞、纤维母细胞和肌纤维母细胞等不同方向分化，构成了恶纤组复杂多样的细胞成分。     

Retinoblastoma cell differentiation in culture

Human retinoblastoma cells were grown in tissue culture and their differentiation into Flexner-Wintersteiner rosettes was investigated. This process of photoreceptor cell differentiation was only observed in primary cultures and subsequent cell passages of tumors which showed these structures in vivo. Rosettes formed spontaneously within 5-9 d after plating of the tumor cells. Under optimal conditions in certain tumor cell strains, up to 80% of the cultured cell aggregates contained one or more differentiated Flexner-Wintersteiner rosettes. Exposure of retinoblastoma cells to RA or dcAMP did not alter the number of rosettes in culture. Retinoblastoma cells within rosettes continued to synthesize DNA, and mitotic figures were frequently observed in histological sections. Ultrastructural analysis of rosettes formed in vitro showed many of the characteristics described in those found in vivo including a polarized shape, established cell junctions (Zonula adherens), extensive accumulation of mitochondria and microtubules in the apical part of the cells, numerous basal bodies and centrioles as well as cilia typical of the mature photoreceptor cell. Lamellated stacks of membranes were also found and their nature is discussed.     

Malignant giant cell tumor of soft parts. An ultrastructural study of four cases.

Four cases of malignant giant cell tumor of soft parts (MGCT) were studied ultrastructurally. Most of the cells in three cases were identified as undifferentiated mesenchymal cells and mononuclear monohistiocytic cells. The osteoclastlike cells seemed to arise from fusion of monohistiocytic cells. Immature fibroblastic cells, occasionally containing filaments with densities, were also present. They were scarce in three cases and predominant in the fourth. It was concluded that MGCT is a mesenchymal sarcoma with a bimorphic--monohistiocytic and fibroblastic--differentiation. MGCT is therefore considered a special variant of malignant fibrous histiocytoma.     

Effector and suppressor lymphoid cells in tumor-bearing guinea-pigs.

The immune reaction of guinea-pigs against their growing tumors was studied. Strain 13 guinea-pigs were killed 2 weeks after SC implantation of the transplantable methylcholanthrene-induced sarcoma (MC-D), when the tumor was 2–3 cm In diameter. Spleen, lymph-node, bone-marrow and peripheral blood leukocytes (PBL), and subsets of spleen cells and PBL were mixed with lethal doses (10⁵) of tumor cells and inoculated SC into normal recipients. Spleen, lymph-node and bone-marrow cells either enhanced or did not influence tumor growth, while PBL exerted a strong inhibitory effect. Normal spleen and normal PBL did not affect tumor growth. The spleen cells of tumor-bearing animals were separated on nylon wool columns: the first fraction containing T cells was responsible for tumor enhancement, the second fraction containing predominantly non-T (Ia⁺) cells inhibited tumor growth. Adherent cells had no effect. Similarly, after removal of T cells from the spleens with a specific rabbit antiserum or of non-T cells plus a minor portion of T cells with an anti-la serum (produced in strain 2 guinea-pigs), the remaining cell population had, respectively, an inhibitory or an enhancing effect on tumor growth. By contrast, removal of either T or la⁺ cells from PBL eliminated their anti-tumor effect. The major portion of splenic T cells formed EA rosettes. EA rosette-positive cells were restricted to a minor portion of peripheral T lymphocytes. Thus, splenic and peripheral T cells from tumor-bearing animals were different both functionally and according to their surface markers. It is hypothesized that Fc⁺ T cells are suppressors which are triggered by immune complexes.     

Histiocytoid hemangioma of the skin and scapula. A case report with electron microscopy and immunohistochemistry

This report presents the interesting case of a 50-year-old white man with an unusual benign tumor composed predominantly of a proliferation of atypical endothelial cells combined with a variable inflammatory response. This case represents an instance of the recently renamed entity "histiocytoid hemangioma" in which two organ systems are involved. Both skin and bone showed typical lesions. No physical connection jointed the separate lesions. The results of examination by light microscopy, electron microscopy, and immunoperoxidase examination for lysozyme and Factor VIII are reported. The significance of this case is that it supports the concept of classifying similar vascular lesions, despite varied organ system origin, into a single entity, the histiocytoid hemangioma.     

Malignant fibrous histiocytoma of the heart. A case report and review of the literature

A case report of a 28-year-old woman with malignant fibrous histiocytoma (MFH) of the left atrium is presented, and the six previous reports of this rare cardiac tumor are reviewed. A tendency for malignant fibrous histiocytoma of the heart to occur in the left atrium of young women is suggested; this sarcoma's usual location is in the soft tissue of elderly men. The apparent predilection for the left atrium is unique among cardiac malignancies. Careful pathologic study is necessary to differentiate the uniformly fatal MFH of the heart from the more common benign atrial myxoma.